Vanessa Bouskill

Acquired von Willebrand syndrome in paediatric patients with congenital heart disease: challenges in the diagnosis and management of this rare condition

Acquired von Willebrand Syndrome (AVWS) is a bleeding disorder resulting from an acquired deficiency or dysfunction of von Willebrand factor (VWF). It is a rare condition in children with only 113 pediatric cases published in the literature between 1968 and 2009 [1]. Recent data suggest that pediatric AVWS is most frequently found in association with acquired or congenital heart defects [2].

Glanzmann thrombasthenia platelets compete with transfused platelets, reducing the haemostatic impact of platelet transfusions

Glanzmann thrombasthenia (GT) is a severe, rare, predominantly mucocutaneous, autosomal recessive bleeding disorder. GT patients have normal platelet counts and morphology, but show absent/severely reduced platelet aggregation owing to defective function/absence of the fibrinogen receptor glycoprotein (GP) IIb-IIIa (integrin aIIbb3) (George et al, 1990; Nurden & Nurden, 2014). Management of GT involves preventing bleeds where possible plus the expeditious management of bleeds that do occur. For persistent or severe bleeding, despite use of local measures and non-specific haemostatic agents (e.g. anti-fibrinolytic agents) and/or recombinant factor VIIa (rFVIIa; NovoSeven, Novo Nordisk, Bagsværd, Denmark), or for patients undergoing major surgery, platelet transfusions are recommended (Poon et al, 2004). As GT patients have normal platelet counts, a post-transfusion platelet count is of limited predictive value to accurately assess the transfusion response, given normal fluctuations observed in platelet counts within all patients (Male et al, 2006). Thus, there is a need for an easily performed, readily available laboratory measure of the response to platelet transfusions in GT patients to ensure that the patient is not platelet refractory, particularly prior to surgery or when treating a lifethreatening bleed. Laboratory tests that can potentially be used to show improvement in primary haemostasis and/or platelet function include the bleeding time (Jennings et al, 1991), flow cytometry (Nurden et al, 2002; Cesar & Vecino, 2009), and global haemostatic assays, such as thromboelastography or thrombin generation assays (Male et al, 2006). However, these tests suffer from lack of availability and reproducibility, and they do not provide a quick turnaround result as would be required in acute situations. We evaluated the Platelet Function Analyser (PFA-100 ; Siemens, Malvern, PA, USA) as a possible laboratory measure of response to platelet transfusions in four patients with GT (Carcao et al, 1998; Favaloro, 2008). Institutional ethics approval was obtained to conduct the study. All patients (Table I) showed the typical aggregation response defects seen in GT, lacked CD41 (GPIIb) by flow cytometry and were compound heterozygotes for ITGA2B. These four patients underwent PFA-100 testing after platelet transfusions on seven separate occasions for bleeding that failed to respond to local measures along with repeated infusions of rFVIIa and tranexamic acid (five episodes) and prior to wisdom teeth extraction (two episodes) (Table I). For all seven platelet transfusions, no apparent reduction (i.e. improvement) in PFA-100 closure times (CTs) posttransfusion was observed. We assessed whether this lack of improvement in CTs in some of the episodes was due to: (i) low haemoglobin levels, secondary to acute blood loss; or (ii) to the presence of anti-platelet antibodies that caused the patients to be platelet refractory. With respect to these possibilities, it should be noted that in 3/7 episodes, patients demonstrated normal haemoglobin levels and that all four patients had undergone multiple screening tests for the presence of anti-platelet antibodies [both anti-human leucocyte antigen (HLA) and anti-GPIIb-IIIa] using a qualitative solid phase enzyme-linked immunosorbent assay (PAK 12 by GTI diagnostics, Waukesha, WI, USA) designed to detect antibodies to HLA class I antigens and to platelet GPIIb-IIIa, GPIaIIa and GPIb-IX. On all 13 occasions, patients tested negative for anti-HLA and anti-glycoprotein antibodies. Given these results, it is extremely unlikely that the lack of improvement in PFA-100 CTs could have been caused by anti-platelet antibodies. GT patients, when transfused with a standard amount of either pooled or aphaeresis platelets (10 ml/kg; approximately 10 9 10 platelets/kg) will have both circulating endogenous GT platelets and transfused ‘normal’ platelets. Using flow cytometry, Cesar and Vecino (2009) reported that after a single platelet transfusion in a 10-year-old girl with GT, only 17% of circulating platelets were the transfused normal platelets. Consequently, when GT patients are given a standard platelet transfusion in the setting of a bleed, most of the platelets adhering to the injury site will still be the endogenous GT platelets as these are in the majority and not the transfused normal platelets. In this situation, we hypothesize that the GT platelets, that are capable of adhering to sites of vascular injury but then are

Impact of aerobic exercise on haemostatic indices in paediatric patients with haemophilia

UNLABELLED This study investigated the impact of aerobic exercise on laboratory assessments of haemostatic activity in boys (5-18 years of age) with haemophilia A (HA) or B (HB), examining the hypothesis that laboratory coagulation parameters temporarily improve with exercise. Thirty subjects meeting eligibility criteria (19 HA; 11 HB; mean age: 12.8 years) were invited to participate. They underwent a replacement factor washout period and were advised against strenuous activity for three days prior to the planned intervention. At study visit, baseline blood samples were drawn prior to exercise on a stationary cycle ergometer, aiming to attain 3 minutes (min) of cycling at 85 % of predicted maximum heart rate. Blood work was repeated 5 min (t5) and 60 min (t60) post exercise completion. Samples were assessed for platelet count (PC), factor VIII activity ( FVIII C), von Willebrand antigen (VWF:Ag), ristocetin cofactor activity (VWF:RCo) and platelet function analysis (PFA-100); maximum rate of thrombus generation (MRTG) in blood was measured via thromboelastography and plasma peak thrombin generation (PTG) via calibrated automated thrombography. Mean duration of exercise was 13.9 (± 2.6) min. On average, t5 samples showed significant elevation, relative to baseline in PC, FVIII:C, VWF:Ag, VWF:RCo and PTG, while FVIII C, VWF:Ag, VWF:RCo and MRTG were significantly elevated in t60 samples. Within the cohort, participants with severe HA showed no change in FVIII C levels with exercise. The greatest improvement in haemostatic indices was observed in post-adolescent males with mild-moderate HA, who thus represent the group most likely to benefit from a reduction of bleeding risk in the setting of exercise.

An institutional pilot study to investigate physical activity patterns in boys with haemophilia

Haemophilia is a bleeding disorder characterized by musculoskeletal bleeding. Trauma‐induced bleeding into joints and muscles may be associated with participation in physical activities. Recognizing this, persons with haemophilia may limit physical activities to avoid bleeding. The characterization of physical activity profiles (type, intensity, frequency and duration) in children with differing severities of haemophilia has not been well documented. This is required to better understand the relationship between physical activity and bleeding in children with haemophilia.

Idiopathic pulmonary arterial hypertension - a unrecognized cause of high-shear high-flow haemostatic defects (otherwise referred to as acquired von Willebrand syndrome) in children

Acquired von Willebrand syndrome (AVWS) is reported in high‐flow high‐shear congenital cardiac disorders. We hypothesized that the narrowed pulmonary vasculature in idiopathic pulmonary arterial hypertension (IPAH) may induce AVWS. We conducted a cross‐sectional evaluation of children with IPAH. Patients with bleeding symptoms and/or laboratory abnormalities (thrombocytopenia, anomalies in coagulation screening tests) were tested in‐depth for haemostatic defects. Fourteen children were followed with IPAH of which 8 were eligible. Four children exhibited abnormal bleeding scores (International Society on Thrombosis and Haemostasis Bleeding Assessment Tool: 3–5). All 8 patients showed very prolonged platelet function analyser (PFA)‐100 closure times. Six children demonstrated either mild thrombocytopenia or low‐normal von Willebrand factor (VWF) antigen (VWF:Ag) or VWF activity [mean (range), in iu/dl: VWF:Ag: 70 (61–91); VWF activity: 57 (34–70)]. Average VWF collagen binding capacity (VWF:CB) was 64 iu/dl (range: 53–123 iu/dl), with low‐normal VWF activity/VWF:Ag or VWF:CB/VWF:Ag ratios occurring in five patients. All children had normal multimers distribution patterns. One patient underwent a lung transplantation, with normalization of haemostatic abnormalities post‐surgery. Overall, 8 out of 14 children with IPAH had mild to moderate bleeding symptoms and/or laboratory abnormalities in keeping with AVWS. Normalization of the haemostatic defects following lung transplantation and lack of family history of bleeding attests to the acquired nature of their defects.

Type 3 VWD and an inhibitor to VWF: Challenges in diagnosis

Abstract Developing an inhibitor to von Willebrand factor (VWF) is extremely uncommon. Consequently, patients with von Willebrand disease (VWD) tend not to be routinely evaluated for inhibitors, leading to the possibility of delay in inhibitor diagnosis. We present such an occurrence to raise awareness, with a view to avoiding such delays. A 1-year-old male with no family history of bleeding disorders or parental consanguinity presented with a tongue bleed lasting three days. Investigations confirmed a diagnosis of Type 3 VWD. Over the next few months, the patient received seven exposures to Humate-P (a plasma derived FVIII containing von Willebrand factor concentrate), but developed an anaphylactic reaction necessitating adrenalin and Benadryl (diphenhydramine). The reaction quickly abated and did not recur with further exposure to Humate-P. In 2013, due to recurrent epistaxis and tonsillar bleeding, the patient was commenced on prophylaxis receiving Humate-P 50 RCo U/kg twice weekly. Despite this regimen, he continued to experience recurrent epistaxis, leading to escalation of prophylaxis to 3/week. In November 2014, he showed persistent tonsillar bleeding, despite having received two doses of Humate-P (each 40 RCo U/kg) in the previous 12 hours. Testing revealed reduced VWF:Ag, VWF:RCo and FVIII:C recoveries. Further testing revealed an anti-VWF antibody (2.6 BU) of unspecified Ig type. Since diagnosis of the inhibitor, he has received 100 RCo U/kg daily for prophylaxis and immune tolerance. He is now bleed-free; however, monthly inhibitor testing shows that his inhibitor persists. Given the limited experience and literature on inhibitors in VWD, the prognosis for such cases is unknown.